With Gene Therapy, VentriNova Aims to Mend Broken Hearts

When a baby is born, a pretty important type of gene shuts down. The gene that carries the instructions for making the heart does its job when the baby is in the womb, and it turns off when the baby is born. That gene is everything to a tiny New York-based startup named VentriNova, because it just might hold the key to repairing a damaged heart.

VentriNova, a startup based around the work of Icahn School of Medicine at Mount Sinai regenerative medicine director Hina Chaudhry, is attempting to develop a gene therapy procedure that would help regenerate cardiomyocytes, or muscle cells, in the hearts of patients who have suffered heart attacks. The idea is essentially in its infancy: VentriNova has only tested an early form of this gene therapy in preclinical animal studies, most recently in pigs. It is likely several years away from having the chance to prove the therapy works in humans in a big clinical trial. And plenty of other academics are trying to harness stem cell technologies to accomplish a similar feat. But Chaudhry says that VentriNova has been able to do something none of them have as of yet—produce new cardiac muscle cells in the injured heart of a large animal.

“There has been no approach to date that can actually create new cardiomyocytes in the diseased heart other than ours,” she says.

It’s the first significant step in what will be a long journey for Chaudhry’s VentriNova to show these findings can lead to a truly significant therapy, the kind that could be used to start to undo the damage caused by a heart attack.

VentriNova—a virtual company consisting of Chaudhry and acting chief operating officer Howard B. Johnson, one of the founding investors of Acorda Therapeutics—originally came together in 2006. That was when Chaudhry, then an assistant professor at Columbia University, was looking into genes that control the development of the heart. Since the genes that instruct the heart’s muscle cells to form are turned off at birth, they can’t be mobilized to turn back on and regenerate dead heart muscle after a heart attack. It’s not like other part of anatomy that are better at healing, like a cut on your skin. When the heart scars, it doesn’t recover.

“These genes are silent in the heart after birth,” she says. “This is the reason we have so much morbidity and mortality from heart attacks and heart disease. We can’t regenerate those tissues.”

Chaudhry wanted to find a way to switch that process back on again. She homed in on a gene, CCNA2, that expresses a protein called cyclin A2. First, she used transgenic mice to see what the difference would be if she flipped the switch, so to speak, and turned cyclin A2 back on. The genetically modified mice, she says, were showing signs of active cyclin A2 proteins. She then induced heart attacks in those mice, and saw evidence that even after heart tissue was damaged, new heart muscle cells were regenerating, she says.

That encouraged Chaudhry to try to create a company, and harness cyclin A2 for a therapeutic. She incorporated VentriNova, and turned to gene therapy to create a treatment. The plan is to load genetically engineered CCNA2 into a virus, and deliver it to the heart with an injection, where it can transmit the protein to the damaged area, and in theory, induce cells to divide.

thread a catheter into a patient’s ventricle, map the area to find the damaged tissue, and inject the drug directly into it. Another idea is to inject it directly to the damaged areas of the heart—a procedure that would require surgery. VentriNova prefers the first approach, and will move forward with it assuming preclinical tests show it works just as well as a direct injection. The procedure would be done within three weeks after a patient has a heart attack, according to Chaudhry.

But while most everyone in gene therapy uses an adeno-associated virus (AAV) or a lentivirus to deliver their treatments, VentriNova selected an adenovirus as a vector. Chaudhry says this is for safety precautions: though she used an AAV vector on some pigs in her preclinical work, she saw that cyclin A2 was being expressed in other organs, including the liver. Because of these results, she says the potential toxicity issues in people are “more concerning” with an AAV than with an adenovirus because an adenovirus dies off in four to six weeks after treatment, whereas an AAV lasts much longer.

“If the virus lives forever it can go wandering into the wrong tissues. That is what we saw when we delivered the AAV to pigs,” she says. “With an AAV, you get lifelong expression of the virus and you get genome integration, so there could be all sorts of problems.”

Even so, Barrie Carter, the vice president who oversees gene therapy at San Rafael, CA-based BioMarin Pharmaceutical (NASDAQ: BMRN), is skeptical of the vector choice. He notes that AAVs have been used so far in a large number of trials and has shown “little to no toxicity,” and that its integration frequency is “actually very low.”

“The fact remains that there clearly is the potential for toxicities with adeno vectors,” he says. “All else being equal, I’d probably pick an AAV.”

Still, based on her findings so far, Chaudhry has been charging forward with the adenovirus. She tested the method in adult rats, and found similarly encouraging results: following a one-time dose administered after a heart attack, heart muscle cells in the rats began dividing, and common measures of heart strength, like its ability to pump out blood (referred to as ejection fraction), improved.

After a few years of “learn[ing] the ropes” of being a scientific entrepreneur, not just an academic, Chaudhry was able to get her work funded. The National Institutes of Health awarded her $500,000 in grant money in 2009, and Boston-based Broadview Ventures put in $1 million in equity financing shortly thereafter. That cash gave her the financial runway to conduct a large animal study at her current lab at Mount Sinai.

In the study, Chaudhry and other researchers induced heart attacks in pigs, and then administered either the cyclin A2 therapy, or a sham treatment, a week later. Researchers found a roughly 18 percent increase in the cardiac function of the pigs that underwent the therapy, compared to a 4 percent decrease in the cardiac function of the pigs that didn’t. Those results were measured six weeks after a single dose, according to Chaudhry.

Now, VentriNova can begin to head for the critical proving ground—clinical trials. VentriNova’s trying to raise about a $5 million Series A round to do bankroll all the preclinical work, such as toxicity and other studies, needed to get it in position to begin clinical trials. Chaudhry estimates it’ll be 18 to 24 months before VentriNova verifies its proof-of-concept study, completes its toxicity work, and gets the green light from the FDA to begin its first trial. Despite the journey ahead, and the wealth of competitors using stem cell technology, Chaudhry is optimistic that her approach will win out.

“I just think we have better results, and a more targeted approach that is based on what nature does as opposed to going against nature,” she says, referring to stem cell approaches. “This [therapy] is mimicking the pathways found in nature already.”